Obesity is an important risk factor for type 2 diabetes mellitus (T2DM), which is a major public health problem in the U.S. Bariatric surgery is currently the most effective weight loss therapy for obesity. Furthermore, Roux-en-Y gastric bypass (RYGB) is most commonly performed bariatric procedure in the US and worldwide and results in resolution of T2DM in ~80% of patients. It has been suggested that the duration of T2DM diagnosis before RYGB surgery is a predictor for diabetes resolution. However, this hypothesis has never been adequately evaluated in human subjects. Therefore, the primary purpose of this proposal is to provide a better understanding of the effect of bariatric surgery-induced weight loss on insulin action and pancreatic -cell function as it relates to the duration of T2DM diagnosis (recent vs. longstanding). We hypothesize that the weight loss provided by RYGB surgery will have greater effects on insulin sensitivity and -cell function in severely obese wit recently diagnosed T2DM than those with longstanding disease. The following specific aims will be evaluated in two groups of severely obese patients with T2DM undergoing RYGB surgery: 1) obese patients with recently diagnosed T2DM (d 5 years) and 2) obese patients with longstanding T2DM (e 10 years). Metabolic studies will be performed before RYGB and repeated after subjects have lost ~ 20% of total body weight. Specifically we aim to: 1. Evaluate the effect of weight loss after RYGB on insulin action in liver (suppression of glucose production), skeletal muscle (stimulation of glucose uptake) and adipose tissue (suppression of lipolysis). This aim will be evaluated by conducting a two-stage hyperinsulinemic euglycemic clamp procedure, in conjunction with stable isotopically-labeled tracer infusion. and 2. Evaluate the effect of RYGB induced weight loss on pancreatic -cell response. This aim will be evaluated by conducting a Mixed Meal Tolerance Test (MMTT), in conjunction with stable isotope tracer ingestion and infusion, to assess absorption of ingested glucose, suppression of endogenous glucose production, and insulin secretion in response to the meal. The achievement of these aims will provide important physiological and clinical knowledge regarding the effect of bariatric (RYGB) surgery on T2DM as it relates of the duration of this condition. Successful completion of this study could influence the current clinical guidelines for the selection of patients for bariatric surgery. The achievement of these aims will provide important physiological and clinical knowledge regarding the effect of bariatric (RYGB) surgery on T2DM as it relates of the duration of this condition. The results from this study could influence curren clinical practice guidelines for the selection of patients who have T2DM for bariatric surgery based on the duration of disease. PUBLIC HEALTH RELEVANCE: Obesity is an important risk factor for type 2 diabetes mellitus (T2DM), which is a major public health problem in the U.S. Bariatric surgery is currently the most effective weight loss therapy for obesity that results in resolution of T2DM in ~80% of patients. We aim to determine the effects of surgical induced weight loss on glucose metabolism as it relates to the duration of T2DM diagnosis (recent vs. longstanding).